OVERVIEW: What every practitioner needs to know#
Are you sure your patient has Stevens–Johnson syndrome/toxic epidermal necrolysis? What should you expect to find?
Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe reactive blistering diseases along a continuum of disease severity. They are uncommon to rare conditions in the general population with increased incidence in the human immunodeficiency virus (HIV)-positive population. Though SJS/TEN is most commonly associated with exposure to medications, SJS is also associated with herpes virus or Mycoplasma. The onset of the disease ranges from 1 to 3 weeks after initiation of the culprit drug.
Prodrome: fever, sore throat, malaise, influenza-like symptoms; 2 to 3 days before skin manifestations
Skin: rash, skin pain, blisters
Mucous membranes (mouth, esophagus, eyes, urogenital, rectal/anal, respiratory): oral pain, odynophagia, decreased oral intake, photophobia, ocular pain, red eyes, dysuria, vaginal pain, painful defecation, nasal discharge/crusting, cough
Key physical findings:
Skin (Figure 1):
Several presentations may be seen:
Erythematous, dusky, or purpuric macules progress to:
atypical targetoid lesions with purpuric centers followed by desquamation
desquamation without the atypical target stage
Purpuric atypical targets coalesce into bullae followed by desquamation
Confluent macular erythema or dusky redness is wide-spread on the trunk followed by gray discoloration as the epidermis necrosis then sloughs
Blisters are flaccid when present (Figure 2)
Face and trunk are initial sites of involvement most often, palms and soles may be an early site of involvement
Maximum body surface area (BSA) reached within 4 days
Estimating BSA: count only skin that is currently denuded or “detachable” with or without Nikolsky’s sign, not purely erythematous skin
SJS covers less than 10% of the patient’s BSA
SJS/TEN overlap covers 10 to 30% of the BSA
TEN covers more than 30% of the BSA
Nikolsky’s sign (slight rubbing of seemingly intact skin results in exfoliation) is positive
Mucous membranes: SJS nearly always has two or more mucous membrane surfaces involved
Hemorrhagic crust on vermilion lips
Erosions and/or ulcers on any surface
Conjunctivitis, often purulent
Crusting along lid margins
Erosions, ulcers, vesicles, bullae
Erosions, ulcers, vesicles, bullae
Hemorrhagic crust at nares
Erythema, erosions, ulcers of nasal mucosae
Inspiratory crackles, rhonchi with auscultation
Hypovolemia to shock
Ill- to toxic-appearing
May have hepatosplenomegaly
Swollen, tender joints
How did the patient develop Stevens–Johnson syndrome/toxic epidermis necrolysis?
Nearly all cases of TEN and most of cases of SJS are caused by exposure to a medication, prescribed or over-the-counter. Some cases of SJS, less than 50%, are caused by infection; herpes or Mycoplasma being the most common.
SJS: 1.2 to 6.0 cases per million person-years
TEN: 0.4 to 1.2 cases per million person-years
HIV: 100 to 1,000 times more common per drug exposure
Drugs implicated: (this is a short list of more common culprits)
Sulfonamides: sulfamethoxazole, sulfadoxine, sulfadiazine, sulfasalazine
Anticonvulsants: lamotrigine (1 in 1,000 adults), carbamazepine (14 in 100,000 adults), phenytoin, barbiturates
Allopurinol (most common cause in Europe)
Nonsteroidal anti-inflammatory drugs (NSAIDs): piroxicam, ibuprofen, naproxen
Which individuals are of greater risk of developing Stevens–Johnson syndrome/toxic epidermal necrolysis?
cluster of differentiation (CD)4 count 25 to 200
Human leukocyte antigen (HLA)-DRB1*0101 patients
Associated with nevirapine induced SJS/TEN and other severe drug reactions
5 to 10% of Asians (not associated in other ethnicities)
Associated with carbamazepine induced SJS/TEN
Han Chinese, Japanese, Thai, and less so in Europeans
Associated with SJS/TEN from allopurinol
Women are at greater risk of SJS/TEN than men
Older age (likely related to exposure to more medications)
Beware: there are other diseases that can mimic Stevens–Johnson syndrome/toxic epidermal necrolysis:
Staphylococcal scalded skin syndrome
More common in newborns and young children
Spares mucous membranes and palms and soles
Caused by an exotoxin directed toward desmoglein resulting in superficial erosions
Acute graft-versus-host disease (GVHD)
Allogeneic stem cell transplantation recipients are at a substantially greater risk of acute GVHD than autologous stem cell transplantation recipients.
Can be difficult to differentiate clinically and histologically
Acute generalized exanthematous pustulosis (AGEP)
Drug-induced skin eruption
Quick onset: 1 to 11 days after exposure
Scarlatiniform erythema; rapid evolution of numerous small nonfollicular pustules
Rarely: purpuric atypical targets; histopathology suggests AGEP over SJS/TEN
Mucous membrane involved but it is nonerosive; typically only one region
Face may be involved
Superficial desquamation occurs in approximately 2 weeks
Not associated with sulfonamides
Underlying non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, sarcoma, thymoma
Severe oropharyngeal erosions/ulcerations
Skin may have erythematous macules, lichenoid papules, targetoid lesions, vesicles/bullae, or erosions
Histopathology and direct immunofluorescence are helpful in establishing the diagnosis
Red papules progress to “target lesions”
Pruritic or burning
Usually not painful
Acral predominance (hands, feet, palms, soles)
Prodrome is uncommon
Oral lesions tend to be discrete and may appear “targetoid”
What laboratory studies should you order and what should you expect to find?
Results consistent with the diagnosis of SJS/TEN
Complete blood count with differential
Leukocytosis is common; may have leukopenia
Eosinophilia (approximately 20%)
Complete metabolic panel
Elevated aspartate aminotransferase and/or alanine transaminase may be seen
Elevated blood urea nitrogen and creatinine
Decreased bicarbonate indicating metabolic acidosis
Elevated sedimentation rate
Cultures if indicated
Blood, urine, skin, sputum
Results that confirm the diagnosis
The diagnosis of TEN is most commonly made clinically. However, in cases where the diagnosis is unclear for either SJS or TEN, skin biopsy may be helpful. When the diagnosis is needed quickly, frozen sections can be invaluable.
Histopathology of skin biopsy specimen
Scattered necrotic keratinocytes to full thickness epidermal necrosis
Lymphocytic inflammatory infiltrate: sparse to dense
What imaging studies will be helpful in making or excluding the diagnosis of Stevens–Johnson syndrome/toxic epidermal necrolysis?
There are no standard radiologic studies for SJS/TEN. Imaging should be based on symptoms and signs on a case-by-case basis.
What consult service or services would be helpful for making the diagnosis and assisting with treatment?
Dermatology can be extremely helpful in evaluating patients with suspected SJS/TEN. Dermatology will help establish the diagnosis clinically or obtain a skin biopsy sample and will aid in determining the culprit drug. Hospitals with established inpatient dermatology consult services experienced in treating patients with SJS/TEN may have improved outcomes.
Intensive care unit (ICU) care in a specialized “burn unit” has shown improved mortality and transfer to such care should be strongly considered when greater than 15% of BSA is involved.
Ophthalmology should be consulted to evaluate for corneal ulcerations and for treatment recommendations.
Gynecology may be consulted for evaluation of the vaginal mucosae.
If you decide the patient has SJS/TEN, what therapies should you initiate immediately?
Key principles of therapy:
Discontinued offending agent as soon as possible (estimated reduced mortality by 30% per day when the offending drug is stopped early)
In general medications that were started within the 4 weeks prior to symptom onset are the likely culprit
Stop ALL nonessential medications
If doubt exists regarding the culprit drug, stop ALL medications
Obtain consultations early
Transfer to specialized “burn” ICU if greater than 15% of BSA is involved; likely reduces infection and mortality
Supportive therapy is essential: intravenous fluids, electrolyte replacement, temperature regulation, and nutritional support
Gentle skin care with as little manipulation and movement as possible
Pay particular attention to mucous membranes’ treatment
Monitor for infection/sepsis and treat early if present
Use of systemic medications for treatment is controversial
Immunosuppressives, if used, should be
Initiated very early in the disease process (once most of the skin has been lost, these medications only contribute to increased mortality)
Considered as a short course to arrest progression
Discontinued if progression of disease is seen
Use of systemic antibiotics should be reserved for those with documented infections or signs/symptoms of sepsis.
Dependent on surface area involved
Peripheral intravenous catheters (placed in uninvolved skin if possible) are preferred to central lines in the hopes of decreasing catheter-related bacteremia
Maintain warm environment: 30 to 32°C
Utilization of the gastrointestinal tract with a feeding tube for example is preferred to parenteral feeding
Analgesia with opiates may be required, particularly when the involved BSA is large
Monitor for signs/symptoms of sepsis: hypotension, hypo- or hyperthermia, altered mental status, worsening glucose control, etc.
Monitor for respiratory compromise: dyspnea and marked hypoxemia even in the setting of a normal chest radiograph may indicate bronchial injury and the need for mechanical ventilation.
Monitor complete blood count, renal function, liver transaminases, and electrolytes frequently
Limit movement and manipulation, limit shearing forces
Bed with controlled pressure (avoid foam and water mattresses) and thermoregulation may be helpful (e.g., air-fluidized bed from Clinitron®)
Removal of necrotic epidermis to reduce risk of infection and subsequent sepsis
Commonly occurs in the operating room using warm saline or sterilized water without detergent
Topical antibiotic application
Silver-sulfadiazine 1% cream is commonly used directly on the wounds
Theoretical risk of renal failure; may delay epithelialization
If sulfonamide is culprit drug, recommend NOT using this cream
Mupirocin 2% ointment
Safety when applied to greater than 20% of BSA has not been established
Silver impregnated dressings are another option
Cover with petrolatum impregnated gauze (Vaseline®, Xeroform®—3% bismuth tribromophenate)
Gentle cleansing with (0.05% chlorhexidine, 0.5% silver nitrate, boric acid, aluminum acetate, or gentian violet) solution with dressing changes
Biobrane®: bilaminar membrane applied after initial debridement of necrotic epidermis then left in place
Reduces pain, improves mobilization, and decreases infection in elderly patients with TEN
Calcium-sodium alginate dressings
Can be left in place for 2 to 3 days
Nanocrystalline silver dressings (Acticoat®, Aquacel®-Ag)
Left in place for 5 to 7 days
Applied in the operative room after debridement of necrotic epidermis; small areas may be covered at the bedside
Stapled in place
Monitored daily for dehiscence and subxenograft purulent material indicting infection
Left in place until dessicated when it is trimmed as epithelialization occurs beneath the xenograft
Glycerol-preserved homologous donor skin is applied at bedside or operating room
Stitched or stapled in place
Covered by petrolatum impregnated gauze that is changed daily
Daily cleansing of eyelids with warm sterile saline
Liberal use of lubricants; may contain antibiotic
Topical antibiotic eye drops: gentamicin
Saline compresses to lips followed by petrolatum or antibiotic ointment to reduce crusting
Rinse mouth several times per day with chlorhexidine solution and/or sterile saline
Viscous lidocaine to reduce pain
Liberal use of petroleum jelly or petroleum impregnated gauze to erosions on vulva/labia to prevent scarring
Daily cleansing of nostrils with warm sterile saline using a cotton tipped swab
Apply topical antibiotic ointment to nares (e.g., mupirocin)
Humidified oxygen when required
If I am not sure what pathogen is causing the infection what anti-infective should I order?
Medications and other treatments used in an attempt to arrest progression of the disease are summarized in
Table I. The use of these treatment modalities is controversial.
|Corticosteroids||When used early in the disease process and at high pulsed doses (dexamethasone 100mg IV daily for 3 to 4 days, methylprednisolone 30mg/kg/day IV for 3 days), they may provide minimal benefit in SJS/TEN. There are case series suggesting benefit, those suggesting no benefit, and those showing detrimental effects including increased mortality.The use of corticosteroids is not recommended by most in patients with TEN.|
|IVIg||The available data suggest that when used early in the disease and reaching a total dose of >2g/kg over 3 to 4 days, there may be a reduction in mortality. One such regimen would include the following: 1g/kg IV daily for 3 to 4 days.Be sure to check for IgA deficiency prior to the use of IVIg to prevent anaphylaxis.|
|Ciclosporin||Case reports and one case series of patients with TEN suggest that this treatment may lead to arrest of progression of skin disease within 36 hours of initiation of the medication and the epidermis may re-epithelialize more quickly. Treatment regimens vary from 3-5mg/kg orally or IV daily from 8 to 24 days. There is theoretical biological basis for its use but more data is needed to recommend it routinely.|
|Plasmapheresis||Small case series results are mixed and this treatment modality cannot be recommended with confidence.|
|One randomized study using thalidomide 400mg daily for 5 days was stopped early due to excess mortality in the thalidomide group.Anecdotal evidence exists for etanercept and infliximab in the setting of TEN showing prompt termination of disease progression. In all cases treated with etanercept and all but two with infliximab, the patients were also treated with corticosteroids.More data is needed to establish TNF-α inhibitors as beneficial in SJS/TEN.|
Ig, immunoglobulin; IV, intravenously; IVIg, intravenous immunoglobulin; SJS, Stevens–Johnson syndrome; TEN, toxic epidermis necrolysis; TNF, tumor necrosis factor.
Evaluation of the literature regarding the treatment of SJS/TEN is limited by lack of adequate control data, uniformity in treatment regimens, and small sample sizes.
There are no studies specifically evaluating the treatment of SJS/TEN in those who are infected with HIV.
What complications could arise as a consequence of Stevens–Johnson syndrome/toxic epidermal necrolysis?
Initiate appropriate antibiotics for documented infection
Empiric antibiotics should cover primarily Staphylococcus aureus
Eyes: approximately 50% of patients will experience some ocular sequelae
Symblepharon or ankyloblepharon
Ectropion and entropion
Aberrant lashes may cause corneal abrasions
Skin and Nails
Adult respiratory distress syndrome (ARDS)
Pneumonia (at times ventilator associated)
Chronic decreased diffusion capacity
Acute renal failure
Stenosis leading to dysphagia and ileus-like symptoms
What should you tell the family about the patient's prognosis?
The prognosis depends on several factors including BSA involved, comorbidities, age, and several signs of systemic disease at the time of admission.
Score of toxic epidermal necrosis (SCORTEN) scale: 1 point is given for each risk factor (Table II).
|Prognostic factor||Points||SCORTEN||Mortality rate (%)|
Age >40 years
Heart rate >120 beats per minute
Cancer or hematologic malignancy
Body surface area >10% on day 1
Serum urea >10mmol/L
|1||> or = 5||90|
Serum bicarbonate <20mmol/L
Serum glucose >14mmol/L
Overall mortality ranges from 1 to 9% in SJS and 25 to 35% in TEN.
Respiratory tract involvement is another poor prognostic indicator.
The most common cause of death in patients with SJS/TEN is infection.
Once the initial insult has occurred and the skin has sloughed, re-epithelialization typically begins fairly quickly from the edge of the ulcerations and from adnexal structures. The average time to re-epithelialization is 3 weeks.
How do you contract Stevens–Johnson syndrome/toxic epidermal necrolysis and how frequent is this disease?
SJS: 1.2 to 6.0 cases per million person-years
TEN: 0.4 to 1.2 cases per million person-years
HIV: 100 to 1,000 times more common per drug exposure
Though SJS is most commonly caused by exposure to medications, it can be seen in the setting of infection as well.
What is responsible for this disease?
Though the exact pathophysiology of SJS/TEN is only partially understood, evidence suggests that cytotoxic T cells initiate the disease resulting in keratinocyte apoptosis followed by necrosis and sloughing. The cell-mediated immune response is felt to be the result of an antigenic complex composed of drug metabolites and host tissues. Granzyme B has been implicated but this requires cell-to-cell contact for killing and in most histologic sections of SJS/TEN, the cellular infiltrate is minimal compared to the level of epidermal necrosis. As such, a soluble cytokine likely plays a role. The most likely culprits include Fas ligand (FasL) and granulysin. FasL and its cognate death receptor Fas, are both upregulated on keratinocytes in TEN. Granulysin, secreted by cytotoxic T cells, natural killer (NK) cells, and NKT cells, is a cytolytic protein and is likely involved in keratinocyte death in TEN. Tumor necrosis factor (TNF) is also elevated in patients with TEN which may explain why TNF-α inhibitors have shown some success in treatment.
In HIV+ patients, there is a relative decrease in CD4+ Tcells, including regulatory Tcells, compared with non-HIV infected patients. This may contribute to the significantly increased risk of developing SJS/TEN in HIV+ patients.
What other clinical manifestations may help me to diagnose and manage Stevens–Johnson syndrome/toxic epidermal necrolysis?
It is very important when seeing a patient with SJS/TEN to meticulously evaluate all medications used in the past 4 to 6 weeks. If the culprit drug cannot be identified, stopping ALL medications should strongly be considered.
What other additional laboratory studies may be ordered?
Should be directed by signs and symptoms
How can Stevens–Johnson syndrome/toxic epidermal necrolysis be prevented?
If prescribing carbamazepine to a patient of Asian ethnicity (except Japanese), obtain HLA testing for HLA-B*1502
In HIV-positive patients it is felt that starting at lower doses of nevirapine may be helpful
WHAT'S THE EVIDENCE for specific management and treatment recommendations?
Lebargy, F, Wolkenstein, P, Gisselbrecht, M. “Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study”. Intensive Care Med. vol. 23. 1997. pp. 1237-44. (Prospective trial showing that a normal chest radiograph when accompanied by other signs or symptoms may still portend a poor prognosis and ventilation requirement.)
Chave, TA, Mortimer, NJ, Sladden, MJ, Hall, AP, Hutchinson, PE. “Toxic epidermal necrolysis: current evidence, practical management, and future directions”. Br J Dermatol. vol. 153. 2005. pp. 241-53. (Review of TEN including pathophysiology and treatment options.)
Boorboor, P, Vogt, PM, Bechara, FG, Alkandari, Q, Aust, M, Gohritz, A, Spies, M. “Toxic epidermal necrolysis: use of Biobrane for skin coverage reduces pain, improves mobilization and decreases infection in elderly patients”. Burns. vol. 34. 2008. pp. 487-92. (Comparative study of Biobrane and paraffin gauze in 14 patients with TEN.)
Barvaliya, M, Sanmukhani, J, Patel, T, Paliwal, N, Shah, H, Tripathi, C. “Drug-induced Stevens–Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap: a multicentric retrospective study”. J Postgradmed. vol. 57. 2001. pp. 115-19. (Review of tertiary care hospitals cases of SJS/TEN focusing on causative drugs, clinical outcome, and cost.)
James, WD, Berger, TG, Elston, DM. “Andrews' Diseases of the Skin”. 2011. pp. 297-301. (Excellent review of SJS/TEN based on the literature.)
Reiger, A, Chen, TM, Cockerell, CJ, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Chapter 77. Cutaneous manifestations of HIV infection and HIV-related disorders”. Dermatology. vol. 1171. 2008. (Detailed review of SJS/TEN including pathophysiology, epidemiology, clinical manifestations, and treatment.)
Williams, J, Coulson, I, Lebwohl, MG, Heymann, WR, Berth-Jones, J. “Treatment of Skin Disease Comprehensive Therapeutic Strategies”. Seborrheic eczema. 2010. pp. 694-6. (This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A: double-blind studies, B: clinical trial with greater than or equal 20 subjects, C: clinical trial with less than 20 subjects, D: case series of more than four subjects, and E: anecdotal case reports.)
Paquet, P, Piérard, G. “Topical treatment options for drug-induced toxic epidermal necrolysis (TEN)”. Expert Opin Pharmacother. vol. 11. 2010. pp. 2447-58. (Excellent review of peer-reviewed literature on topical therapies used in the treatment of TEN.)
The typical length of stay will depend on BSA involved and complications that occur during the hospitalization. Hospitalizations ranging from 5 to 30 days are commonly reported.
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- OVERVIEW: What every practitioner needs to know#
- Are you sure your patient has Stevens–Johnson syndrome/toxic epidermal necrolysis? What should you expect to find?
- How did the patient develop Stevens–Johnson syndrome/toxic epidermis necrolysis?
- Which individuals are of greater risk of developing Stevens–Johnson syndrome/toxic epidermal necrolysis?
- Beware: there are other diseases that can mimic Stevens–Johnson syndrome/toxic epidermal necrolysis:
- What laboratory studies should you order and what should you expect to find?
- What imaging studies will be helpful in making or excluding the diagnosis of Stevens–Johnson syndrome/toxic epidermal necrolysis?
- What consult service or services would be helpful for making the diagnosis and assisting with treatment?
- If I am not sure what pathogen is causing the infection what anti-infective should I order?
- What complications could arise as a consequence of Stevens–Johnson syndrome/toxic epidermal necrolysis?
- What should you tell the family about the patient's prognosis?
- How do you contract Stevens–Johnson syndrome/toxic epidermal necrolysis and how frequent is this disease?
- What is responsible for this disease?
- What other clinical manifestations may help me to diagnose and manage Stevens–Johnson syndrome/toxic epidermal necrolysis?
- What other additional laboratory studies may be ordered?
- How can Stevens–Johnson syndrome/toxic epidermal necrolysis be prevented?
- WHAT'S THE EVIDENCE for specific management and treatment recommendations?